D-3-phosphoglycerate dehydrogenase (PHGDH) in humans catalyzes the first step of serine biosynthesis and is a key enzyme in the serine synthesis pathway. PHGDH was shown to be overexpressed in 40% of melanoma and 70% of triple negative breast cancer cells in 2011. Knockout experiments with the PHGDH gene revealed that the growth of these cancer cells was greatly inhibited [(1) Locasale, J. W., et al. (2011). Nat. Genet. 43, 869-874. (2) Possemato, R., et al. (2011). Nature 476, 346-350.]. Therefore, using PHGDH as an anti-cancer target for drug design has a broad prospect. Because the active pocket of PHGDH is small, the physiological concentration of the cofactor NAD+ is as high as 0.3 mM, and the complete crystal structure of PHGDH has not been solved yet, drug design based on PHGDH active pocket goes slowly. The new strategy is to carry out allosteric regulation of PHGDH and design allosteric inhibitors of PHGDH.
Allosteric regulation in proteins refers to the phenomenon that allosteric effectors bind to the inactive sites of the protein and cause changes of the protein activity. Allosteric drugs showed better properties by increasing selectivity, regulating the activity of the target protein without complete loss of protein activity, only exhibiting allosteric ability in the presence of endogenous ligand, etc.
Recent studies have identified PHGDH gene knockdown combined with cisplatin or doxorubicin can significantly increase the biological activity of these anti-cancer drugs in vitro and in vivo [(3) Jing, Z., et al. (2015). Cancer Biol. Ther. 16, 541-548. (4) Zhang, X., and Bai, W., (2016). Cancer Chemother. Pharmacol. 78, 655-659.]. The studies provide reference for cancer therapy using the combination of PHGDH inhibitors and anti-cancer drugs. Till now, there is no report for PHGDH inhibitors in clinical research or the drug effects of PHGDH inhibitors combined with other anti-cancer drugs. Carrying out drug design targeting allosteric sites of PHGDH and using allosteric inhibitors for tumor prevention and treatment is novel and creative.